The present invention relates to novel polymorphic Forms XI, XII, XIII, XIV, XV and XVI of sertraline hydrochloride, to processes for preparing them, methods of using them to treat disease, methods of using them to make other sertraline hydrochloride forms, and to pharmaceutical dosages containing the novel forms.
Sertraline hydrochloride, (1S-cis)-4-(3,4 dichlorophenyl)-1,2,3,4-tetrahydro-N-methyl-1-naphthalenamine hydrochloride, having the formula 
is approved, under the trademark Zoloft(copyright), by the U.S. Food and Drug Administration, for the treatment of depression, obsessive-compulsive disorder and panic disorder.
U.S. Pat. No. 4,536,518 (xe2x80x9cthe ""518 patentxe2x80x9d) describes the preparation of sertraline hydrochloride with a melting point of 243-245xc2x0 C. by treating an ethyl acetate/ether solution of the free base with gaseous hydrogen chloride. The solid state properties of the sertraline hydrochloride so produced are not otherwise disclosed.
According to U.S. Pat. No. 5,248,699 (xe2x80x9cthe ""699 patentxe2x80x9d), the sertraline hydrochloride produced by the method of the ""518 patent has a crystalline form denominated xe2x80x9cForm II.xe2x80x9d The ""699 patent discloses four other polymorphs designated Forms I, III, IV, and V.
The present invention includes new polymorphic forms of sertraline hydrochloride. Polymorphic forms of a compound can be distinguished in a laboratory by X-ray diffraction spectroscopy and by other methods such as, infrared spectrometry. It is desirable to investigate all solid state forms of a drug, including all polymorphic forms, and to determine the stability, dissolution and flow properties of each polymorphic form. For a general review of polymorphs and the pharmaceutical applications of polymorphs see G. M. Wall, Pharm Manuf. 3, 33 (1986); J. K. Haleblian and W. McCrone, J. Pharm. Sci., 58, 911 (1969); and J. K. Haleblian, J. Pharm. Sci., 64, 1269 (1975), all of which are incorporated herein by reference.
Commonly-assigned, co-pending U.S. patent application Ser. No. 09/448,985 filed Nov. 24, 1999, which is incorporated herein by reference, discloses novel methods of making sertraline hydrochloride Form V that were discovered after unsuccessful attempts at sublimation. One of the methods disclosed in that application involves crystallization from an acidic hexane and/or isopropanol solvent system that can be made acidic by addition of concentrated hydrochloric acid in lieu of gaseous hydrochloric acid. The co-pending application also discloses other new sertraline hydrochloride forms that have been designated Forms VI, VII, VIII, IX and X.
The present invention relates to novel forms of sertraline hydrochloride. The present invention provides processes for preparing sertraline hydrochloride Forms XI, Form XII, Form XIII, Form IV, Form XV and Form XVI; compositions containing sertraline hydrochloride Forms XI-XVI; methods of using sertraline hydrochloride Forms XI-XVI to prepare other forms of sertraline hydrochloride and methods of using sertraline hydrochloride Forms XI-XVI to treat depression, obsessive-compulsive disorder and panic disorder.
The present invention relates to sertraline hydrochloride Form XI which is characterized by a powder X-ray diffraction pattern comprising peaks at about 16.0xc2x10.2, 17.7xc2x10.2, 20.7xc2x10.2, 24.9xc2x10.2 and 29.2xc2x10.2 degrees two-theta. Sertraline hydrochloride Form XI of the present invention is also characterized by an infrared spectrum comprising absorption bands at 739, 1040, 1201, 1560 and 1595 cmxe2x88x921.
The present invention also relates to a process for making sertraline hydrochloride Form XI comprising the steps of: (a) dissolving sertraline hydrochloride in benzyl alcohol to form a sertraline hydrochloride solution; (b) crystallizing sertraline hydrochloride Form XI from the sertraline hydrochloride solution; and (c) isolating the sertraline hydrochloride Form XI.
The present invention also relates to sertraline hydrochloride Form XI where sertraline hydrochloride Form XI is sertraline hydrochloride Form XI benzyl alcohol solvate.
The present intention also relates to sertraline hydrochloride Form XI benzyl alcohol hemi-solvate, sertraline hydrochloride Form XI benzyl alcohol mono-solvate, sertraline hydrochloride Form XI benzyl alcohol di-solvate and sertraline hydrochloride Form XI benzyl alcohol tri-solvate.
The present invention also relates to a method of making sertraline hydrochloride Form X comprising the step of heating sertraline hydrochloride Form XI.
The present invention also relates to sertraline hydrochloride Form XII which is characterized by a powder X-ray diffraction pattern comprising peaks at about 4.3xc2x10.2, 12.0xc2x10.2, 13.4xc2x10.2, 16.3xc2x10.2, and 17.4xc2x10.2 degrees two-theta.
The present invention also relates to a process for making sertraline hydrochloride Form XII comprising the steps of: (a) exposing sertraline hydrochloride to water vapor; and (b) isolating sertraline hydrochloride Form XII. In another embodiment of the invention, the process for making sertraline hydrochloride Form XII comprises the steps of: (a) exposing sertraline hydrochloride Form V to water vapor; and (b) isolating sertraline hydrochloride Form XII. The present invention also relates to sertraline hydrochloride Form XII hydrates, including sertraline hydrochloride Form XII mono-hydrate.
The present invention also relates to sertraline hydrochloride Form XIV which is characterized by a powder x-ray diffraction pattern comprising peaks at about 7.4xc2x10.2, 9.6xc2x10.2, 12.0xc2x10.2, 12.8xc2x10.2, 14.3xc2x10.2, 16.0xc2x10.2, 16.2xc2x10.2, 18.0xc2x10.2, 21.1xc2x10.2, 23.2xc2x10.2, 23.6xc2x10.2, 24.3xc2x10.2, 24.9xc2x10.2, 25.7xc2x10.2, 26.7xc2x10.2, 29.6xc2x10.2 and 32.5xc2x10.2 degree two-theta.
The present invention also relates to a process for making sertraline hydrochloride Form XIV comprising the steps of: (a) dissolving sertraline base in a solvent mixture of methanol and hexane to form a solution of sertraline base and the solvent; (b) adding hydrogen chloride to the solution to attain a pH of from about 0.5 to about 1.5; (c) precipitating sertraline hydrochloride from the solution; (d) removing the solvent; and (e) isolating sertraline hydrochloride Form XIV.
The present invention also relates to a process for making sertraline hydrochloride Form XIV comprising the steps of: (a) adding sertraline hydrochloride Form II to methanol to form a suspension of solid sertraline hydrochloride in methanol; and (b) isolating sertraline hydrochloride Form XIV.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: (a) heating sertraline hydrochloride Form XIV; and (b) isolating sertraline hydrochloride Form V.
The present invention also relates to sertraline hydrochloride Form XIII which is characterized by a powder X-ray diffraction pattern comprising peaks at about 8.5xc2x10.2, 13.3xc2x10.2, 14.0xc2x10.2, 15.3xc2x10.2, 16.3xc2x10.2, 17.5xc2x10.2, 20.1xc2x10.2, 21.5xc2x10.2, 22.5xc2x10.2, 23.6xc2x10.2, 25.0xc2x10.2 and 25.9xc2x10.2 degrees two-theta.
The present invention also relates to a process for making sertraline hydrochloride Form XIII comprising the steps of: (a) heating sertraline hydrochloride Form XIV; and (b) isolating sertraline hydrochloride Form XIII.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: (a) heating sertraline hydrochloride Form XIII; and (b) isolating sertraline hydrochloride Form V.
The present invention also relates to sertraline hydrochloride Form XV which is characterized by a powder x-ray diffraction pattern comprising peaks at about 6.5xc2x10.2, 10.7xc2x10.2, 12.9xc2x10.2, 14.2xc2x10.2, 15.2xc2x10.2, 16.6xc2x10.2, 17.5xc2x10.2, 18.1xc2x10.2, 19.9xc2x10.2, 20.4xc2x10.2 24.0xc2x10.2 and 24.5xc2x10.2 degrees two-theta.
The present invention also relates to a process for making sertraline hydrochloride Form XV comprising the steps of: (a) dissolving sertraline base in a solvent comprising a mixture of isopropanol and a non-polar solvent to form a solution of sertraline base; (b) adding aqueous hydrochloric acid to the solution of sertraline base to facilitate precipitation of sertraline hydrochloride Form XV; (c) removing the solvent; and (d) isolating sertraline hydrochloride Form XV. Preferably, the non-polar solvent is hexane.
The present invention also relates to a process for making sertraline hydrochloride Form XV comprising the steps of: (a) adding sertraline base to isopropanol; (b) adding aqueous hydrochloric acid to the mixture of sertraline base and isopropanol in an amount sufficient to form sertraline hydrochloride; (c) heating the mixture of sertraline hydrochloride and isopropanol to facilitate complete dissolution of sertraline hydrochloride; (d) adding water to the mixture to facilitate complete dissolution of sertraline hydrochloride; (e) stirring the mixture for a time sufficient to induce the transformation to sertraline hydrochloride Form XV; and (f) isolating sertraline hydrochloride Form XV.
The present invention also relates to a process for making sertraline hydrochloride Form V comprising the steps of: (a) heating sertraline hydrochloride Form XV; and (b) recovering sertraline hydrochloride Form V.
The present invention also relates to sertraline hydrochloride Form XVI which is characterized by a powder X-ray diffraction pattern comprising peaks at about 15.6xc2x10.2, and 23.0xc2x0xc2x10.2xc2x0 degrees two-theta.
The present invention also relates to a process for preparing sertraline hydrochloride Form XVI comprising the steps of: (a) dissolving sertraline base in a solvent wherein the solvent is selected from the group consisting of hexane, cyclohexane and toluene to form a mixture of sertraline base and the solvent; (b) adding hydrogen chloride to the mixture to attain a pH of from about 1 to about 1.5; (c) precipitating sertraline hydrochloride Form XVI from the mixture; (d) removing the solvent; and (e) isolating sertraline hydrochloride Form XVI.
The present invention also relates to processes for preparing sertraline hydrochloride Form II comprising the steps of: (a) adding sertraline hydrochloride Form XIV to a solvent selected from the group consisting of ethyl acetate, acetone, and t-butyl-methyl-ether to form a suspension of sertraline hydrochloride; (b) heating the suspension; (c) stirring the suspension for a time sufficient to transform sertraline hydrochloride Form XIV to sertraline hydrochloride Form II; and (d) isolating sertraline hydrochloride Form II. Preferably, by these methods, the suspension is heated to a temperature range of about 25xc2x0 C. to reflux, and more preferably the suspension is heated to reflux. The process further comprises the step of cooling the suspension prior to isolating sertraline hydrochloride Form II.
The present invention also relates to processes for preparing sertraline hydrochloride Form II comprising the steps of: (a) adding sertraline hydrochloride Form XV to a solvent selected from the group consisting of ethyl acetate, acetone, t-butyl-methyl-ether and cyclohexane to form a suspension of sertraline hydrochloride; (b) stirring the suspension for a time sufficient to transform sertraline hydrochloride Form XV to sertraline hydrochloride Form II; (c) heating the suspension; and (d) isolating sertraline hydrochloride Form II. Preferably, by these methods, the suspension is heated to a temperature range of about 25xc2x0 C. to reflux, more preferably, the suspension is heated to reflux. The process further comprises the step of cooling the suspension prior to isolating sertraline hydrochloride Form II. Preferably, the suspension is cooled to a temperature range of about 25xc2x0 C. to about 5xc2x0 C.
The present invention also relates to a process for preparing sertraline hydrochloride Form II comprising the steps of: (a) adding sertraline hydrochloride Form XVI to a solvent selected from the group consisting of ethyl acetate and acetone to form a suspension of sertraline hydrochloride; (b) heating the suspension to facilitate the transformation for sertraline hydrochloride Form XVI to sertraline hydrochloride Form II; and (c) isolating sertraline hydrochloride Form II.
The present invention also relates to a pharmaceutical composition comprising a therapeutically effective amount of sertraline hydrochloride selected from the group consisting of: sertraline hydrochloride Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, and mixtures thereof, and a pharmaceutically acceptable vehicle.
The present invention also relates to a method for treating depression comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of sertraline hydrochloride selected from the group consisting of: sertraline hydrochloride Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, and mixtures thereof.
The present invention also relates to a method for treating obsessive-compulsive disorder comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of sertraline hydrochloride selected from the group consisting of: sertraline hydrochloride Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, and mixtures thereof.
The present invention also relates to a method for treating panic disorder comprising the step of administering to a patient in need of such treatment a therapeutically effective amount of sertraline hydrochloride selected from the group consisting of: sertraline hydrochloride Form XI, Form XII, Form XIII, Form XIV, Form XV, Form XVI, and mixtures thereof.
Sertraline hydrochloride Form XI, Form XII, Form XII, Form XIV, Form XV and Form XVI are useful in the preparation of pharmaceutical compositions which are particularly useful for treatment of depression, obsessive-compulsive disorder and panic disorder.
Sertraline hydrochloride Form XI has the advantage of providing the preservative, benzyl alcohol, and sertraline hydrochloride in the same step and has the advantage of simplifying the formulation process by omitting a separate addition step and potentially more accurately controlling the quantity of benzyl alcohol since a larger quantity of material is measured than when the preservative is added separatively.
Sertraline hydrochloride Form XIV, Form XV and Form XVI are useful for preparing sertraline hydrochloride Form II.
Sertraline hydrochloride Form XIV and Form XV are useful for preparing sertraline hydrochloride Form V.